The present invention relates to novel compounds, pharmaceutical compositions containing said compounds and their use in the treatment of various CNS disorders.
Dementia exists in several forms including static dementia, Alzheimer""s-type dementia, senile dementia, presenile dementia and progressive dementia. One of the common pathological features of several types of dementia is the lack of the neurotransmitter acetylcholine. This has led to the development of acetylcholine esterase inhibitors for use in the treatment of dementias such as the compound tacrine. A summary of the different approaches to and progress made in the treatment of Alzheimer""s Disease may be found in Drugs of the Future (1995) 20(11): 1145-1162.
Recently, compounds that in addition to inhibiting acetylcholine esterase, possess inhibitory activity against monoamine oxidase type A (MAO-A) have been developed. The perceived benefit of having the anti-MAO-A activity is stated to be an anti-depressant effect (European Patent Publication Nos. 614,888 and 664,291).
U.S. Pat. Nos. 5,387,133, 5,453,446, 5,457,133 and 5,519,061 all disclose that the compound (R)-N-propargyl-1-aminoindan, a highly selective monoamine oxidase type B (MAO-B) inhibitor is effective in the treatment of dementias of the Alzheimer type and memory disorders. There is no indication given therein that the compound might have acetylcholine esterase inhibitory activity. Furthermore, the compound is only very weakly active as a MAO-A inhibitor.
PCT International Publication No. WO95/18617 discloses various aminoindan derivatives that are active in a variety of CNS disorders including dementias of the Alzheimer type. There is no indication given therein that any of the compounds disclosed might have acetylcholine esterase inhibitory activity.
The present invention relates to compounds of formula I: 
wherein when a is 0; b is 1 or 2; when a is 1, b is 1; m is from 0 to 3; X is O or S; Y is halogeno; R1 is hydrogen or alkyl; R2 is hydrogen, C1-4 alkyl or optionally substituted propargyl; and R3 and R4 are each independently hydrogen, C1-8 alkyl, C6-12 aryl, C6-12 aralkyl or C6-12 cycloalkyl optionally substituted.
The invention relates to the compounds themselves, pharmaceutical compositions containing said compounds and their use in the treatment of depression, Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD), Tourette""s Syndrome, Alzheirner""s Disease and other dementias such as senile dementia, presenile dementia, progressive dementia, dementia of the Parkinson""s type, vascular dementia and Lewy body dementia.
A further aspect of the present invention relates to the use of the compounds of formula I in the treatment of neurotraumatic disorder. As used herein the term xe2x80x9cneurotraumatic disorderxe2x80x9d is meant to include damage caused to the nervous system (both central and peripheral) by virtue of ischemic damage such as that which occurs in stroke, hypoxia or anoxia, neurodegenerative diseases, Parkinson""s Disease, Alzheimer""s Disease, Huntington""s Disease, neurotoxic injury, head trauma injury, spinal trauma injury, peripheral neuropathy or any form of nerve damage.
An additional aspect of the present invention relates to the use of the compounds of formula I in the treatment of memory disorder or depression.
The present invention relates to the racemic compounds themselves and optically active enantiomers thereof.
FIG. 1 shows the reduction in latency for mice after closed head injury in the Morris Water Maze Test after treatment with compound 1, compound 10 or Saline (Control). The arrow shows the time of closed head injury.
FIG. 2 shows the reduction in latency for mice after closed head injury in the Morris Water Maze Test after treatment with compound 24, compound 25 or Saline (Control). The arrow shows the time of closed head injury.
FIG. 3 shows the reduction in latency for mice after closed head injury in the Morris Water Maze Test after treatment with compound 37, compound 39 or Saline (Control). The arrow shows the time of closed head injury.
The present invention is directed to compound of Formula I: 
wherein when a is 0, b is 1 or 2; when a is 1, b is 1, m is from 0-3, X is O or s; Y is halogeno; R1 is hydrogen or C1-4 alkyl; R2 is hydrogen, C1-4 alkyl, or optionally substituted propargyl and R3 and R4 are each independently hydrogen, C1-8 alkyl, C6-12 aryl, C6-12 aralkyl or C6-12 cycloalkyl each optionally substituted.
In an embodiment of the present invention, a is 0 and b is 1. In another embodiment of the present invention, a is 0, b is 1, and X is O.
In an embodiment of the present invention, X is 0. In an additional embodiment of the present invention, X is S.
In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen, methyl, ethyl or optionally substituted propargyl.
In another embodiment of the present invention, R2 is propargyl.
In a further embodiment of the present invention, the compound is selected from the group consisting of: (rac) 6-(N-methyl, N-ethyl-carbamyloxy)-Nxe2x80x2-propargyl-1-aminoindan HCl; (rac) 6-(N,N-dimethyl, carbamyloxy)-Nxe2x80x2-methyl-Nxe2x80x2-propargyl-1-aminoindan HCl; (rac) 6-(N-methyl,N-ethyl-carbamyloxy)-Nxe2x80x2-propargyl-1-aminotetralin HCl; (rac)6-(N,N-dimethyl-thiocarbamoyloxy)-1-aminoindan HCl; (rac)6-(N-propyl-carbamyloxy)-Nxe2x80x2-propargyl-1-aminoindan HCl; (rac)5-chloro-6-(N-methyl, N-propyl-carbamyloxy)-Nxe2x80x2-propargyl-1-aminoindan HCl; (S)-6-(N-methyl, N-propyl-carbamyloxy)-Nxe2x80x2-propargyl-1-aminoindan HCl; and (R)-6-(N-methyl, N-ethyl-carbamyloxy)-Nxe2x80x2-propargyl-1-aminoindan hemi-(L)-tartrate.
In a further embodiment of the present invention, R1 is hydrogen, methyl or ethyl and R2 is hydrogen, methyl, ethyl or optionally substituted propargyl. In a further embodiment of the present invention, the propargyl group is substituted with a C1-4 alkyl group on the methylene group (R6 in Scheme I).
According to the present invention, the term xe2x80x9chalogensxe2x80x9d is used to refer to fluoro, chloro, bromo, or iodo.
In an embodiment of the present invention, when m is greater than 1 each Y may be the same or different.
In an additional embodiment of the present invention, the group OC(X)NR3R4 is on the 4, 6 or 7 position of the indan ring counting from the amino substituted carbon.
In another embodiment of the present invention, at least one of R3 and R4 is methyl and the other is hydrogen, methyl, ethyl, propyl, butyl, hexyl, phenyl, benzyl or cyclohexyl.
In the practice of this invention, pharmaceutically acceptable salts include, but are not limited to, the esylate, mesylate, maleate, fumarate, tartrate, hemi-tartarate, hydrochloride, hydrobromide, p-toluenesulfonate, benzoate, acetate, phosphate and sulfate salts.
The subject invention further provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of formula I or a pharmaceutically acceptable salt thereof may be determined according to methods well known to those skilled in the art, indications of such amounts are given below.
These compositions may be prepared as medicaments to be administered orally, parenterally, rectally, or transdermally.
Suitable forms for oral administration include tablets, compressed or coated pills. dragees, sachets, hard or soft gelatin capsules, sublingual tablets, syrups and suspensions. In one embodiment, the pharmaceutically acceptable carrier is a solid and the pharmaceutical composition is a tablet. The therapeutically effective amount may be an amount from about 0.5 mg to about 2000 mg, preferably from about 1 mg to about 1000 mg.
In an alternative embodiment, the pharmaceutically acceptable carrier is a liquid and the pharmaceutical composition is an injectable solution. The therapeutically effective amount may be an amount from about 0.5 mg to about 2000 mg, preferably from about 1 mg to about 1000 mg. The volume administered may be an amount between 0.5 and 10 ml.
In a further alternative embodiment, the carrier is a gel and the pharmaceutical composition is a suppository. For parenteral administration the invention provides ampoules or vials that include an aqueous or non-aqueous solution or emulsion. For rectal administration there are provided suppositories with hydrophilic or hydrophobic vehicles. For topical application as ointments and transdermal delivery there are provided suitable delivery systems as known in the art. For oral or suppository formulations, 0.5-2000 mg per dosage unfit and preferably 1-1000 mg per dosage unit.
These compositions may be used alone to treat the above-listed disorders, or alternatively, for example, in the case of Alzheimer""s Disease, they may be used as an adjunct to the conventional treatments such as haloperidol, tacrine or deprenyl.
The invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.